Vascular cell adhesion molecule-1 (VCAM-1) is a protein that is found on the surface of endothelial cells that line the interior wall of capillaries. VCAM-1 recognizes and binds to the integrin .alpha..sub.4 .beta..sub.1 (or VLA-4 for very late antigen-4), a heterodimeric protein present on the surface of certain white blood cells. Binding of .alpha..sub.4 .beta..sub.1 to VCAM-1 allows white blood cells to adhere to the capillary wall in areas where the tissue surrounding the capillary has been infected or damaged.
When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells recognize the invaded or damaged tissue, bind to the wall of the capillary near the affected tissue and diffuse through the capillary into the affected tissue. VCAM-1 helps certain types of white blood cells recognize the affected sites, bind to the capillary wall, and migrate into the affected tissue.
There are three main types of white blood cells: granulocytes, monocytes and lymphocytes. VCAM-1 binds to .alpha..sub.4 .beta..sub.1 expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes--eosinophils and basophils.
Monocytes, after leaving the bloodstream through the wall of a capillary, mature into macrophages that phagocytose and digest invading microorganisms, foreign bodies and senescent cells. Lymphocytes produce antibodies and kill infected cells. Eosinophils and basophils secrete mediators of various inflammatory reactions.
Following infection or damage of tissue surrounding a capillary, the endothelial cells that line the capillary express a series of adhesion molecules, including VCAM-1, that are critical for binding white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1, the white blood cells initially bind to another set of adhesion molecules to slow their flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 on the endothelial cells via the .alpha..sub.4 .beta..sub.1 integrin. There is evidence that this interaction is also involved in transmigration of these white blood cells into the damaged tissue.
Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, would be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to VCAM-1.
For example, some of the diseases that might be treated by the inhibition of .alpha..sub.4 .beta..sub.1 binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis and type I diabetes. In addition to being found on some white blood cells, .alpha..sub.4 .beta..sub.1 is found on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving .alpha..sub.4 .beta..sub.1 may be involved in the metastasis of certain cancers. Inhibitors of .alpha..sub.4 .beta..sub.1 binding may, therefore, also be useful in the treatment of some forms of cancer.